title: EGF-like growth factors induce COX-2-derived PGE2 production through ERK1/2 in human granulosa cells.
abstract: BACKGROUND
  Aberrant regulation of ovulation is one of the major causes of infertility. In animal models, 3 epidermal growth factor (EGF)-like growth factors, amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG), have been shown to be involved in ovulation by regulating cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. However, whether the same is true in humans remains largely unknown.
  
  
  OBJECTIVE
  Our objective was to investigate the effects of AREG, BTC, and EREG on COX-2 expression and PGE2 production in human granulosa cells.
  
  
  METHODS
  SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with SV40 large T antigen. SVOG cells were used to investigate the effect of AREG, BTC, and EREG on ovulation-related functions at an academic research center.
  
  
  METHODS
  Levels of mRNA and protein were examined by quantitative RT-PCR and Western blotting, respectively. The protein levels of PGE2 were measured by ELISA.
  
  
  RESULTS
  LH treatment upregulated AREG, BTC, EREG, and COX-2. Knockdown of EGF receptor (EGFR) attenuated LH-induced COX-2 expression and PGE2 production. Treatment with AREG, BTC, and EREG upregulated COX-2 expression and PGE2 production. The stimulatory effects of AREG, BTC, and EREG on COX-2 expression and PGE2 production were blocked by inhibition of EGFR activity and expression. AREG-, BTC-, and EREG-activated ERK1/2 signaling, but not Akt signaling, was required for AREG-, BTC-, and EREG-induced COX-2 expression and PGE2 production.
  
  
  CONCLUSIONS
  AREG, BTC, and EREG induced PGE2 production by upregulating COX-2 expression through ERK1/2 signaling in human granulosa cells.
authors.affiliation: PhD, FCAHS, FRSC, Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Room 317, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. peter.leung@ubc.ca.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Fang
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Ying-Pu
authors.initials: YP
authors.lastname: Sun
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D066258:Amphiregulin; D066259:Betacellulin; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D066255:EGF Family of Proteins; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006107:Granulosa Cells / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism; D020935:MAP Kinase Signaling System; D034622:RNA Interference; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587851:BTC protein, human; D066259:Betacellulin; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D007986:Luteinizing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D015232:Dinoprostone